David M. O'MAlley

Opposing roles of the glucocorticoid receptor pathway in lymphoid cancers versus solid tumors and its clinical implications

Glucocorticoid receptor antagonists assessed in patients with various solid tumors

Glucocorticoid receptor (GR) signaling is critical to our physiology but is dysregulated in cancer by the pain, psychologic distress, iatrogenic morbidity, and pathology associated with an advanced, invasive disease. Many tumors exploit glucocorticoid signaling to provide antiapoptotic survival signals, stimulate growth and metastasis, suppress immune surveillance, and drive treatment resistance. Endogenous cortisol and exogenous glucocorticoids are typically associated with poor responses to cytotoxic chemotherapy, targeted therapy, and immunotherapy in patients with solid tumors. Translational and nonclinical data show that selective GR antagonists (SGRA) synergize with anticancer agents, including taxanes, androgen receptor inhibitors, PARP inhibitors, and anti–programmed cell death ligand 1 (PDL-1) immune checkpoint inhibitors, driving improved anticancer activity. In a tumor-intrinsic manner, SGRAs downregulate the antiapoptotic proteins SGK1 and DUSP1, which induce resistance to cytotoxic chemotherapy. This synergy has been confirmed in several randomized controlled trials, which showed improved efficacy when SGRAs were added to standard-of-care taxane therapy in platinum-resistant ovarian cancer. In a distinct cellular context, SGRAs inhibit resistance to antiandrogen therapy mediated through the GR and have the potential for additive anticancer activity in prostate cancer. Herein, we summarize the role of glucocorticoid signaling in solid tumor biology, providing mechanistic insights into recent clinical advances and emphasizing key outstanding translational and clinical questions.

Glucocorticoid receptor (GR) signaling is critical to our physiology but is dysregulated in cancer by the pain, psychological distress, iatrogenic morbidity, and pathology associated with an advanced, invasive disease. Many tumors exploit glucocorticoid signaling to provide anti-apoptotic survival signals, stimulate growth and metastasis, suppress immune surveillance, and drive treatment resistance. Endogenous cortisol and exogenous glucocorticoids are typically associated with poor responses to cytotoxic chemotherapy, targeted therapy, and immunotherapy in patients with solid tumors. Translational and non-clinical data show that selective GR antagonists (SGRAs) synergize with anti-cancer agents, including taxanes, androgen receptor inhibitors, PARP inhibitors, and anti-PD(L)-1 immune checkpoint inhibitors, driving improved anti-cancer activity. In a tumor-intrinsic manner, SGRAs downregulate the anti-apoptotic proteins SGK1 and DUSP1, which induce resistance to cytotoxic chemotherapy. This synergy has been confirmed in several randomized controlled trials, which showed improved efficacy when SGRAs were added to standard-of-care taxane therapy in platinum-resistant ovarian cancer. In a distinct cellular context, SGRAs inhibit resistance to anti-androgen therapy mediated through the GR and have the potential for additive anti-cancer activity in prostate cancer. Herein, we summarize the role of glucocorticoid signaling in solid tumor biology, providing mechanistic insights into recent clinical advances and emphasizing key outstanding translational and clinical questions.

PERK and other potential biomarkers of therapy response in LGSOC. A, pERK IHC examples demonstrating negative (0), weak (1+), moderate (2+), and intense (3+) positivity for histoscore calculation. Scale bars, 50 µm. B, Response to trametinib (top) and physician’s choice SOC (bottom) according to KRAS/BRAF/NRAS mutation status (left), pERK status (middle), and chr1 abnormalities (right). C, pERK histoscore according to KRAS/BRAF/NRAS mutation type. Labels specify the numbers within each group that were evaluable for pERK expression levels. D, pERK histoscore by chr1p-loss status. E, Frequency of pERK status between chr1p-loss and -intact groups. Chr1pq-aberrant, chr1p-loss with concurrent chr1q-gain.

Study case flow diagram for WES of translational specimens from patients enrolled in GOG281. One hundred thirty-four samples underwent successful WES, of which 112 were also evaluable for pERK via IHC. Additionally, 36 samples were evaluable for pERK IHC that did not have matching WES.

Molecular landscape of tumor samples from patients enrolled in GOG281/LOGS. MAPK-associated, MAPK-associated genes as defined in the Gene Ontology Term GO:0000165; Chr1pq-aberrant, chr1p-loss with concurrent chr1q-gain.

Purpose:Low-grade serous ovarian carcinoma (LGSOC) is a distinct form of ovarian cancer characterized by younger patient age and relative chemoresistance. The GOG281/LOGS trial (NCT02101788) investigated the efficacy of the MEK inhibitor trametinib compared with physician’s choice standard-of-care (SOC) in patients with LGSOC with persistent/recurrent disease. The study demonstrated significantly improved progression-free survival (PFS) in the trametinib-treated arm.Experimental Design:Two hundred and sixty patients with recurrent/persistent LGSOC were enrolled and randomly assigned in GOG281. We performed molecular analysis of 170 patients with available tumor specimens, comprising whole-exome sequencing and phospho-ERK (pERK) IHC, to identify biomarkers of clinical benefit from trametinib. The demographics of the translational cohort (n = 170) were comparable with those of the total trial cohort.Results:High tumor pERK expression (greater than the median histoscore of 140) was associated with significantly prolonged PFS with trametinib treatment versus SOC (median 20.1 vs. 5.6 months, log-rank P < 0.0001; test for interaction P = 0.023). Tumors harboring canonical RAS–RAF–MAPK mutations (KRAS/BRAF/NRAS: 44/134, 32.8% of cases) had a higher response rate to trametinib (50.0% vs. 8.3%; Barnard’s P = 0.0004; test for interaction P = 0.054), but KRAS/BRAF/NRAS status was not predictive of prolonged PFS (test for interaction P = 0.719). KRAS amplification (n = 5 without KRAS/NRAS/BRAF mutation) and mutation of MAPK-associated genes (n = 25 without KRAS/NRAS/BRAF mutation or KRAS copy number gain) expanded the number of cases with identifiable MAPK defects to 55.2%, but consideration of these events did not improve the discrimination of trametinib responders. Chr1p loss (49% of cases) was associated with lower pERK expression (P = 0.021).Conclusions:This exploratory analysis suggests that pERK expression and mutation of KRAS/BRAF/NRAS are candidate biomarkers of improved PFS and response to trametinib, respectively.

Demographics of translational research population.

Impact of pERK status and KRAS/BRAF/NRAS mutation status on GOG281 patient outcome. A, PFS of GOG281/LOGS patients with low-pERK tumors (pERK ≤ 140) in trametinib versus SOC arms. B, PFS of GOG281/LOGS patients with high-pERK tumors (pERK > 140) in trametinib versus SOC arms. C, PFS of GOG281/LOGS patients with KRAS/BRAF/NRAS WT tumors in trametinib versus SOC arms. D, PFS of GOG281/LOGS patients with KRAS/BRAF/NRAS-mutant tumors in trametinib versus SOC arms. Labeled HR refer to comparison of trametinib versus SOC arm.